Radiation therapy has been a critical part of our approach to cure cancer for almost 100 years. While the technology for radiation delivery has dramatically improved, the ability to personalize radiation treatment based on baseline, genetic differences between patients, has not yet been applied to direct therapy. We have discovered that inherited, germline DNA biomarkers, disrupting microRNA regulatory networks, act as biomarkers of the radiation response, predicting toxicity and the radio-immune response. In this proposal, we will further validate and refine this panel of biomarkers for each of the key radiation endpoints - normal tissue toxicity, tumor control and the radio-immune response. We will use prospectively collected samples from a large clinical patient population treated with current radiation techniques, as well as a Phase I/II trail incorporating anti-PD-L1 therapy with radiation. By the end of this contract, we will have a fullyvalidated panel of biomarkers that can be applied as a test to direct radiation therapy, to minimize toxicity and enhance the potential of radiation to cure cancer. Radiation treatment is a cornerstone of our battle against cancer, and allowing the optimal use of this powerful treatment for each individual patient will have a very broad impact on human health.